Process for making 3,4,5,6-tetrahydrophthalimide derivatives

ABSTRACT

3-(3,4,5,6-tetrahydrophthalimido)cinnamic esters I ##STR1## (R 1  =H, halogen; R 2 , R 3  =halogen; R 4  =C-organic radical, R 5  =H, CH 3 ) are prepared by reducing 3-nitrocinnamic esters II ##STR2## with hydrogen in the presence of a catalyst and condensing the resulting 3-aminocinnamic esters III ##STR3## with a 3,4,5,6-tetrahydrophthalic anhydride IV ##STR4## and are valuable active ingredients in crop protection.

The present invention relates to an improved process for preparing3-(3,4,5,6-tetrahydrophthalimido)cinnamic esters of the formula I##STR5## where R¹ is hydrogen or halogen, R² and R³ are halogen, R⁴ is aC-organic radical of 1 to 6 carbon atoms and R⁵ is hydrogen or methyl.

It is generally known that nitrocinnamic esters which, however, have noalpha halogen are reduced by iron in acetic acid (JP-A 155 358/84) orhydrogen on a palladium, platinum or Raney nickel catalyst (EP-A 345 637and DE-A 39 31 615) to aminocinnamic esters and these are converted intotetrahydrophthalimidocinnamic esters of the type of compounds I.

However, according to Bull. Chem. Soc. Jap. 49, (1976) 2284, BE-A855-464 and EP-A 240 659, when hydrogen is used as reducing agent thereis also hydrogenation of the unsaturated side chain of an aromaticcompound. EP-A 240 659 also discloses that this side reaction does notoccur when platinum oxide is used as catalyst or when metals such asiron are used as reducing agents.

In addition, EP-A 369 212 and Chimia 41, (1987) 73 disclose thatcatalytic dehalogenation is possible with hydrogen in the presence ofcatalysts such as palladium, platinum and Raney nickel, and this is infact used for preparative syntheses in these publications.

It is therefore proposed, to avoid the said competing reactions, in theearlier German Application DE-A 39 31 615 that specifically the3-nitrocinnamic esters II which have alpha chlorine or bromine bereduced only with mild reducing agents such as tin(II) salts or withiron to the 3-amino esters III.

However, the disadvantage of this method is the problem on theindustrial scale of removing and disposing of the tin and iron saltswhich are the byproducts of the reduction.

It is an object of the present invention to provide better access to thecompounds I.

We have found that this object is achieved by a process for preparing3-(3,4,5,6-tetrahydrophthalimido)cinnamic esters of the formula I, whichcomprises reducing a 3-nitrocinnamic ester of the formula II ##STR6##with hydrogen in the presence of a catalyst, and condensing theresulting 3-aminocinnamic ester of the formula III ##STR7## subsequentlyor simultaneously with a 3,4,5,6-tetrahydrophthalic anhydride of theformula IV ##STR8##

We have also found novel 3-nitrocinnamic esters of the formula II'##STR9## where R¹ ' is hydrogen or fluorine, R² and R³ are halogen andR⁴ ' is C₁ -C₄ -alkyl, and novel 3-aminocinnamic esters of the formulaIII' ##STR10## as intermediate.

The 3-nitrocinnamic esters II used as starting materials can be preparedin a variety of ways, preferably by one of the following methods:

(a) reaction of m-nitro aldehydes IV with phosphorus ylides V ##STR11##

The Ar radicals can be identical or different and are C-organicradicals, in particular, phenyl.

The reaction is generally carried out by conventional methods (cf. EP-A345 637) in an inert solvent or diluent, e.g. alcohols, preferably in R⁴--OH, or in chlorohydrocarbons such as dichloromethane.

All the starting compounds are preferably employed in approximately thestoichiometric ratio, but an excess of one component, of up to 10 mol %,may be advisable in some cases.

The reaction is normally carried out at from 0° C. to the boiling pointof the solvent.

No special conditions relating to the pressure are necessary; thereaction is therefore expediently carried out under atmosphericpressure.

The starting compounds IV are known. The phosphorus ylides V can beprepared by conventional methods [e.g. Chem. Ber. 95, (1962) 3003].

(b) Nitration of cinnamic esters VI ##STR12##

The reaction is carried out by conventional methods (cf. also JP-A 155358/84), if required in an inert solvent or diluent at from -10° to 50°C.

The amount of nitration reagent is not critical. It is preferable to usean excess of nitration reagent in sulfuric acid or without solvent innitric acid.

The statements concerning the pressure made for method (a) apply. Thepreparation of the starting compounds can be similar to method (a).

(c) Halogenation of m-nitrocinnamic esters VII ##STR13##

The reaction is generally carried out in a conventional manner (cf. EP-A240 659) in an inert solvent or diluent, e.g. a halohydrocarbon such asmethylene chloride, chloroform, tetrachloromethane,1,1,1-trichloroethane and chlorobenzene.

An excess of halogen (R³)₂ of up to about 10 mol % based on the amountof VI is preferably employed.

The reaction is normally carried out at from 0° C. to the boiling pointof the solvent, in particular from 15° to 40° C.

Once again, atmospheric pressure is advisable.

In the case of the chlorination of the m-nitrocinnamic esters VII, aparticularly advantageous embodiment of method (c) compriseschlorinating the m-nitrocinnamic ester VII in the presence of a Lewisacid and subjecting the resultingα,β-dichloro-β-(2-nitrophenyl)propionic ester (as mixture ofdiastereoisomers) to elimination of hydrogen chloride.

Particularly suitable Lewis acids are transition metal halides such aszinc(II) chloride, iron(III) chloride and aluminum chloride.

Suitable and preferred solvents are chlorohydrocarbons such asdichloromethane and 1,2-dichlorobenzene.

The amount of Lewis acid is not critical; in general from 2 to 200 mol%, preferably 5 to 140 mol %, of Lewis acid, based on the amount ofm-nitrocinnamic ester VII, are used.

To avoid long reaction times, it is advisable to carry out the reactionat from 20° C. to the boiling point of the reaction mixture, inparticular from 50° to 90° C.

The subsequent elimination of hydrogen chloride takes place in thepresence of an auxiliary base, preferably without introducing ordissipating energy.

The stereochemistry of the elimination can be controlled by the choiceof the base, so that the E or Z isomer of the 3-nitrocinnamic esters IIis predominantly obtained.

Examples of suitable auxiliary bases are the alkaline earth metal saltsof organic acids or organic amines. Very particularly preferably used issodium acetate in glacial acetic acid, or triethylamine in methylenechloride, in which case the Z isomer of the 3-nitrocinnamic esters II isthe main product.

The α,β-dichloro-β-(2-nitrophenyl)propionicester and the base arepreferably employed in the stoichiometric ratio, or a small excess ofbase of up to about 10 mol % is used.

The starting compounds VII can be obtained in a similar manner to method(a) or (b).

(d) Reaction of nitrocinnamoyl chlorides VIII with alcohols IX ##STR14##

The reaction is generally carried out in a conventional manner (cf.Houben-Weyl, Methoden der Organischen Chemie, Volume X/2, 747) in aninert solvent or diluent, advantageously in the presence of a base.

Suitable solvents or diluents are, in particular, fairly high-boilinghydrocarbons such as o-, m-or p-xylene and toluene, esters such as ethylacetate, and ethers such as dioxane and tetrahydrofuran.

Suitable and preferred bases are tertiary amines such as triethylamineand pyridine, and inorganic salts, e.g. alkali metal hydroxides such assodium and potassium hydroxide and alkali metal carbonates such assodium carbonate.

The reaction is normally carried out at from -10° to 200° C., inparticular from 0° to 150° C.

The statements concerning the ratios of amounts and the pressure madefor method (a) apply.

The cinnamoyl chlorides VIII can be obtained by conventional methods(cf. EP-A 240 659, Example 8).

The nitrocinnamic acid derivatives II are reduced according to theinvention using hydrogen in the presence of a metal catalyst, e.g.palladium, platinum and nickel, to the corresponding aminocinnamic acidderivatives II.

The reduction is expediently carried out in an inert polar solvent ordiluent, for example an ether such as tetrahydrofuran, an amide such asdimethylformamide, a short-chain carboxylic acid such as acetic orpropionic acid, an ester of a short-chain carboxylic acid such as ethylacetate, or the alcohol HO--R⁴, especially in methanol or ethanol.

The amount of catalyst is not critical; normally, 1 to 50 mol % ofcatalyst based on the amount of nitrocinnamic acid derivative II isused.

The hydrogenation is expediently carried out under a pressure of from 1to 100 bar, preferably from 1 to 10 bar, with hydrogen.

The reaction is generally carried out at from 0° C. to the boiling pointof the solvent.

The process can be carried out either batchwise or continuously. Whencarried out continuously, the nitrocinnamic acid derivative in asolution saturated with hydrogen is preferably passed over a fixed bedwhich has been coated with the catalyst.

In a preferred embodiment, hydrogen is metered into a mixture ofnitrocinnamic acid derivative II, diluent and catalyst until no furtherconsumption of hydrogen is detectable.

The mixture is worked up in a conventional manner so that details onthis are unnecessary.

The resulting 3-aminocinnamic acid derivatives III are subsequentlyconverted by condensation with 3,4,5,6-tetrahydrophthalic anhydrides ofthe formula IV into the 3-(3,4,5,6-tetrahydrophthalimido)cinnamic estersI: ##STR15##

The reaction is normally carried out in an inert aprotic solvent at from20° C. to the boiling point of the solvent, in particular from 40° to140° C.

Suitable solvents are lower alkanoic acids such as glacial acetic acid,propionic acid and isobutyric acid, the esters of the said acids such asethyl acetate, aromatic hydrocarbons such as toluene and o-, m- andp-xylene, and aprotic solvents such as dimethyl- and diethylformamide.When an aprotic solvent is used, continuous removal of the water whichis produced is advisable.

The starting compounds III and IV are expediently employed in thestoichiometric ratio, but an excess of one of the components, of up toabout 10 mol %, may be advisable in some cases.

The reaction is preferably carried out under atmospheric pressure or theautogenous pressure of the solvent. Lower or higher pressure is possiblebut generally has no advantages.

A particularly advantageous variant of the process according to theinvention comprises the products III which have been obtained byreduction of the 3-nitrocinnamic acid derivatives II being reacted withthe 3,4,5,6-tetrahydrophthalic anhydrides IV without isolation from thereaction mixture. It is possible in this procedure for the3,4,5,6-tetrahydrophthalic anhydride IV to be introduced into thereaction mixture before or after the hydrogenation. In this case, thereaction is preferably carried out in a lower alkanoic acid, especiallyin propionic acid, or in an aprotic solvent, especially in an ether suchas tetrahydrofuran or an amide such as dimethylformamide.

The process according to the invention can be used successfully tosynthesize all 3-(3,4,5,6-tetrahydrophthalimido)cinnamic acidderivatives I as defined with α-chlorine or bromine, particularly thosecompounds in which the substituents have the following meanings:

R¹ --hydrogen or halogen such as fluorine, chlorine, bromine and iodine,especially hydrogen or fluorine;

R² --halogen as mentioned above, especially chlorine;

R³ 13 chlorine or bromine;

R⁴ 13 hydrogen;

--C₁ -C₄ -alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl andtert-butyl, and the alkyl can also carry one or two C₁ -C₄ -alkoxyradicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andtert-butoxy, especially methoxy and ethoxy, and/or C₁ -C₄ -alkylthioradicals such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio and tert-butylthio, especially methylthio;

--C₃ -C₇ -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl;

--C₃ -C₆ -alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl,3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl,4-methyl-4-pentenyl,1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl,1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and1-ethyl-2-methyl-2-propenyl;

--C₃ 14 C₆ -alkynyl such as 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl,2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl,1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl,3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl,4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl,1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl,1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and1-ethyl-1-methyl-2-propynyl;

--benzyl;

R⁵ hydrogen or methyl.

The 3-nitrocinnamic acid derivatives II' and the 3-aminocinnamic acidderivatives III' where R¹ ' is hydrogen or fluorine, R² and R³ arehalogen and R⁴ ' is C₁ -C₄ -alkyl as mentioned above are novel.Particularly preferred derivatives II' and III' are those where R² ischlorine and R³ is chlorine or bromine.

3-(3,4,5,6-Tetrahydrophthalimido)cinnamic esters I are used in cropprotection, especially as herbicides (preferably in cereals) and asabscission agents (in cotton).

PREPARATION EXAMPLES(E/Z)-N-[3-(2-chloro-2-ethoxycarbonylvinyl)-4-chlorophenyl]-3,4,5,6-tetrahydrophthalimide##STR16## EXAMPLE 1

456 g (3 mol) of 3,4,5,6-tetrahydrophthalic anhydride were added alittle at a time to a solution of 780 g (3 mol) of ethyl(E/Z)-2,alpha-dichloro-5-aminocinnamate in 7 l of propionic acid at 20°to 25° C. The resulting clear solution was stirred at 60° C. for 5hours, during which the product started to crystallize. The mixture wascooled to about 25° C. and diluted with 4 l of water and then stirredfor at least 14 hours. The product was then separated off, washed with4.5 l of water and dried.

Yield: 80% (purity about 98% by HPLC); melting point: 111°-112° C.

Precursor 1α Ethyl (E/Z)-2,alpha-dichloro-5-nitrocinnamate ##STR17## bymethod (a):

84.1 g (0.22 mol) of ethoxycarbonyl(chloro)methylenetriphenylphosphoranewere added to a solution of 37 g (0.2 mol) of2-chloro-5-nitrobenzaldehyde in 350 ml of ethanol. The mixture wasstirred at 25° C. for one hour, after which the product was filtered offand washed with petroleum ether.

Yield: 70%; melting point 97°-98° C.

by method (c):

0.64 g (4 mmol) of anhydrous iron(III) chloride was added to a solutionof 10 g (39 mmol) of ethyl 2-chloro-5-nitrocinnamate in 150 ml of1,2-dichlorobenzene, after which chlorine was passed in at 100° C. for 3hours. The reaction mixture was subsequently washed with saturatedsodium bicarbonate solution and with water, dried over sodium sulfateand concentrated. Yield: 75% of ethylα,β-dichloro-β-(2-chloro-5-nitrophenyl)propionate (3:1 diastereomermixture); melting point 63°-65° C.

1 g (3 mmol) of the ethyl α,β-dichloro-β-(2-chloro-5-nitrophenyl)propionate obtained above was dissolved in 30 mlof methylene chloride, after which 0.31 g (3 mmol) of triethylamine wasadded to the solution. The mixture was stirred at 20°-25° C. for about15 hours, then washed twice with water, dried with sodium sulfate andconcentrated under reduced pressure.

Yield: 100% of a crude product which still contained 5 to 10% of thedichloro compound.

Precursor 1β Ethyl (E/Z)-2,alpha-dichloro-5-aminocinnamate ##STR18##

3 g (51 mmol) of Raney nickel were added to a suspension of 5.8 g (20mmol) of ethyl (E/Z)-2,alpha-dichloro-5-nitrocinnamate in 150 ml ofethanol. After injection of 1.05 bar of hydrogen, the mixture wasstirred at 30° C. until hydrogen uptake ceased (about 7 hours). Thecatalyst was then separated off, the solvent was removed and the residuewas washed with petroleum ether.

Yield: 77%; melting point 110°-111° C.

EXAMPLE 2 (ONE-STAGE VARIANT)

A mixture of 29 g (100 mmol) of ethyl 2,alpha-dichloro-5-nitrocinnamate,3 g (51 mmol) of Raney nickel, 15.2 g (100 mmol) of3,4,5,6-tetrahydrophthalic anhydride and 100 ml of propionic acid washydrogenated at 50° to 60° C. by injection of 1.05 bar of hydrogen untilhydrogen uptake ceased (about 18 hours). The catalyst was then removedfrom the still hot reaction mixture, and 100 ml of water were added tothe resulting solution. After stirring for 30 minutes, the crystallizedproduct was separated off and washed with water until neutral.

Yield: 85%; melting point 108°-110° C.

We claim:
 1. A process for preparing a3-(3,4,5,6-tetrahydrophthalimido)cinnamic ester of the formula I##STR19## where R¹ is hydrogen or halogen, R² and R³ are halogen, R⁴ ishydrogen, C₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl, C₃ -C₆ -alkenyl, C₃ -C₆-alkynyl or benzyl and R⁵ is hydrogen or methyl, which comprisesreducing a 3-nitrocinnamic ester of the formula II ##STR20## withhydrogen in the presence of a catalyst, and condensing the resulting3-aminocinnamic ester of the formula III ##STR21## subsequently orsimultaneously with a 3,4,5,6-tetrahydrophthalic anhydride of theformula IV ##STR22##
 2. The process of substituted claim 1, wherein thereduction is carried out in a polar solvent.
 3. The process as claimedin claim 1, which starts from a 3-nitrocinnamic ester II as produced inthe preparation of II by halogenation of an m-nitrocinnamic ester of theformula VII ##STR23##
 4. The process as claimed in claim 1, which startsfrom a 3-nitrocinnamic ester II as produced in the reaction of anm-nitro aldehyde IV ##STR24## with a phosphorus ylide V

    Ar.sub.3 P═C(R.sup.3)--CO--OR.sup.4                    V.